PARP is a family of enzymes that catalyzes the addition of an ADP-ribose residue to various target proteins. To date, as many as 18 isoforms have been identified and characterized. Despite the large number of enzymes in the family, PARP-1 is responsible for more than 90% of the ADP-ribosylation within cells.
PARP-1 has long been associated with DNA repair and maintenance of genomic function. Following DNA damage, PARP-1 becomes instantly activated by binding to DNA breaks. After the structural changes, it begins to utilize NAD+ to synthesize poly(ADP) ribose as a signal for the other repairing enzymes (such as DNA ligase III, DNA polymerase beta). This process of PARP-1 binding and activation (known as base excision repair) helps amplify the repair process in which single-strand DNA breaks (SSB) are targeted. SSB are generally initiated by oxidative damages that are caused by cell's own metabolic processes as well as by exogenous chemotherapeutical agents and radiation. It is well-known that many types of anti-cancer therapies, such as DNA alkylating agents, platinum-based drugs, topoisomerase inhibitors and radiotherapy, are concomitant with DNA damages. These therapies are shadowed by the emergence of drug resistance, particularly in PARP-1 dominated DNA repair pathway. Recent studies have confirmed that selective PARP-1 inhibitors greatly enhance the antitumor efficacies of TMZ and cisplatin.
BRCA1 and BRCA2 play an essential role in homologous recombination (HR). DNA breaks arising during DNA replication can only be repaired by HR. In 2005, Bryant and Farmer (Nature, 2005, 913 and 917) independently discovered that cell lines deficient in BACA1 and BACA2 were very sensitive to PARP-1 inhibitors, resulting in cells death. Breast cancer genes BRCA1/2 have long been characterized as tumor suppressor genes that play an indispensable role in the repair of DNA double strand breaks. BRCA1/2 mutation carriers in ovarian cancer and prostate cancer are also at an elevated risk. Therefore PARP-1 inhibitors could also be used as a standalone therapy for such types of tumors that are already deficient in certain types of DNA repair mechanism.
PARP-1 has been an actively pursued oncology target for 30 years and Ferraris has entirely summarized the progress in this field (J. Med. Chem. 2010, 4561). A series compounds are in clinical studies regardless as a single agent or a synergist, such as veliparib (ABT-888), niraparib (MK-4827), BMN-673, CEP-977, BGP-15, E-7016, MP-124 and IND-1022. Recently certain heterocyclic compounds have also been disclosed as being useful in the treatment of a variety of cancers in some patents, for example, WO2014009872 (A1), WO2014019468 (A1), WO2014023390 (A2), WO2013182580, WO2013164061 (A1), EP2656843 (A1).
In addition, PARP-1 inhibition has been an actively pursued drug discovery target in wide ranges of therapeutic areas compassing stroke, cardiac ischemia, inflammation, and diabetes (Pharmacol. Rev. 2002, 54, 375.).
Although efforts have always been made to develop PARP-1 inhibitors for treating cancer and other diseases, satisfactory treatment has not yet been achieved. Thus, there exists a need for the development of new PARP-1 inhibitors.